Although the abuse of opioids has been documented over many centuries, it is largely in the last century that we have been confronted by the abuse of pharmaceutical grade opioids in the form of pharmaceutical dosage forms intended for therapeutic uses. The abuse of opioids is either due to iatrogenic addiction or willful abuse of the products outside their intended use or method of use by drug abusers and recreational drug users.
Currently, medical practitioners may choose from several well-accepted classes of pharmaceutical agents in their attempts to alleviate and prevent pain. Nonlimiting examples of agents used include nonsteroidal anti-inflammatory agents (NSAIDs), e.g., aspirin, ibuprofen, ketoprofen, diclofenac; opioids, e.g., morphine, hydromorphone, hydrocodone, levorphanol, oxycodone, tramadol, and codeine; cyclooxygenase-2 (COX-2) selective NSAIDs, e.g., celecoxib, valdecoxib, etoricoxib, lumiracoxib, and rofecoxib; acetaminophen and nitroparacetamol; tricyclic antidepressants, e.g., amitriptyline, desipramine, nortriptyline; non-tricyclic antidepressants, e.g., doxepin, duloxetine, paroxetine, venlafaxine; antiepileptics, e.g., gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine; voltage sensitive N-type calcium channel blockers, e.g., ziconotide and alpha adrenergic agonists, e.g., clonidine.
An important goal of analgesic therapy is to achieve continuous relief of pain. Regular administration of an analgesic is generally required to ensure that the next dose is given before the effects of the previous dose have worn off. Continuous suppression of pain through the use of around the clock opioid analgesics is now recommended in treatment guidelines (Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Fifth Ed., American, Pain Society (2003); Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Can et al. J Nat Cancer Inst Monograph 2004; 32:23-31; Agency for Health Care Policy and Research Clinical Practice Guidelines for Cancer Pain Management, Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Agency for Health Care Policy and Research Clinical Practice Guideline for Acute Pain Management, Guideline No. 1, AHCPR Publication No. 92-0032, February, 1992; Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005; Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis, 2nd Ed., American Pain Society, 2002).
Conventional (so called “immediate-release”, “rapid release” or “short acting”) opioid analgesics have been demonstrated to provide short-lived plasma levels, thereby requiring dosing every 4-6 hours in chronic pain. In contrast, extended release oral opioids are designed to maintain effective plasma levels throughout a 12 or 24-hour dosing interval. Extended release opioid formulations have now become the standard of care for the management of chronic pain. Use of extended release opioids can result in fewer interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced quality of life outcomes, and increased control over the management of their pain. In addition, such formulations can provide more constant plasma concentrations and clinical effects, less frequent peak to trough fluctuations and fewer side effects, compared with short acting opioids (Babul et al. Journal of Pain and Symptom Management 2004; 28:59-71; Matsumoto et al., Pain Medicine 2005; 6:357-66; Dhaliwal et al., Journal of Pain Symptom Management 1995; 10:612-23; Hays et al., Cancer 1994; 74:1808-16; Arkinstall et al., Pain 1995; 62:169-78; Hagen et al., Journal of Clinical Pharmacology 1995; 35:38-45; Peloso et al., Journal of Rheumatology 2000; 27:764-71).
Several studies have suggested the benefits of extended release over immediate release opioids. Ferrell et al (Oncol Nur Forum 1989; 4:521-6) compared 12-hourly controlled release morphine and short-acting analgesics in cancer pain and demonstrated that compliance increased as the required dosing frequency decreased, and noncompliance resulted in suboptimal pain control and poor quality-of-life outcomes. Arkinstall et al. (Pain 1995; 62:169-78) demonstrated that around that twice daily administration of controlled release codeine provided superior to pain control than a PRN regimen of acetaminophen plus codeine.
An important drawback with the use of opioids is the risk of drug addiction, drug diversion and drug abuse. Although the use of opioids for non-medical purposes has existed throughout recorded human history, their abuse has increased significantly in the past two decades (Drug Abuse Warning Network, http://dawninfo.samhsa.gov/; Drug Enforcement Administration, http://www.deadiversion.usdoj.gov/; National Survey on Drug Use & Health, http://www.oas.samhsa.gov/nhsda.htm; American Association of Poison Control Centers Toxic Exposure Surveillance System, http://www.aapcc.org/annual.htm).
Our increased understanding of the clinical pharmacology of opioids and data from well controlled clinical trials in chronic non-cancer pain (Peloso et al., Journal of Rheumatology 2000; 27:764-71; Caldwell, et al., Journal of Pain and Symptom Management 2002; 23:278-91; Matsumoto et al., Pain Medicine 2005; 6:357-66; Arkinstall et al., Pain1995; 62:169-78) and neuropathic pain (Watson and Babul, Neurology 1998; 50:1837-41) have resulted in more widespread use in patients with non-malignant pain (for a review, see Sloan and Babul, Expert Opinion on Drug Delivery 2006; 3:489-97). This in turn has led to concerns about the increased non-medical use of opioids through both licit and illicit channels. For instance, unsuspecting clinicians may prescribe opioids for pain to individuals with an addiction disorder or individuals with pain who divert a portion of their prescribed dose to other individuals. There have also been documented cases of inappropriate prescribing or dispensing of opioids by physicians and pharmacists, with its eventual diversion into the non-medical marketplace. Additionally, non-medical supplies of pharmaceutical grade opioids are often obtained through prescription forgeries and break-ins into pharmacies.
Pharmaceutical dosage forms containing opioids may be ingested whole, crushed and ingested, crushed or vaporized and snorted or injected intravenously after attempted extraction of the active pharmaceutical ingredient.
The introduction of extended release morphine (MS Contin®) revolutionized the management of cancer pain. MS Contin® gained widespread acceptance due to its global availability, significant pharmacokinetic and pharmacodynamic data, and the convenience of an extended-release formulation. However, the incidence and severity of side effects limits the use of morphine in some patients (Hagen and Babul, Cancer 1997; 79:1428-37). In patients with renal impairment, morphine's principal metabolites, morphine-3-glucuronide and morphine-6-glucuronide can accumulate. Morphine-3-glucuronide accumulation has been implicated in hyperalgesia, respiratory stimulation, and behavioral excitatory properties through nonopioid receptor mechanisms. Morphine-6-glucuronide accumulation has been implicated in increasing levels of nausea and sedation in patients with renal impairment (Babul and Darke, Clin Pharm Ther, 1993; 54:286-92).
Clinicians treating cancer pain with opioids have reported significant variability among patients in efficacy and side effects with available opioid analgesics. Patients with poor analgesic efficacy or safety outcomes on one opioid frequently tolerate another opioid well. This clinical observation led to the development of oxycodone ER (OxyContin®). Due to the limitations associated with extended release morphine noted above and the “stigma” associated with its use (i.e., association with addiction, advanced cancer, dying and death), extended release oxycodone gained rapid acceptance by patients with chronic non-cancer pain. However, its widespread use for the treatment of chronic non-malignant pain was also associated with its diversion into the non-medical supply for use both by addicts and recreational drug users.
The popularity of extended release oxycodone among addicts and recreational drug users was due to a large amount of drug per tablet (a 12 or 24 hour supply). Commercially available immediate release opioid tablets and capsules are usually administered every 4 to 6 hours and they release their dose into the systemic circulation over one to two hours. New, extended release formulations are designed to gradually release their much larger opioid content over a 12 or 24-hour period. Most recreational drug users and addicts have a unit of use which is one tablet or capsule. The 12 or 24-hour supply of opioid contained in one tablet or capsule, instead of 4 to 6 tablets or capsules means that there is a greater risk that such formulations may be highly sought by drug addicts and recreational drug users alike, for non-medical use. Intentional or inadvertent tampering from extended release formulations will rapidly deliver a massive dose and produce profound a variety of serious and life threatening side effects, including respiratory depression and failure, sedation, cardiovascular collapse, coma and death.
Addicts and recreational drug may user extended release opioids by the parenteral, intranasal or oral route. Opioid abuse can involve physical, mechanical, thermal or chemical tampering of the dosage form (e.g., crushing, melting, solvent extraction and filtration)
Scheduling of opioid drugs has also had the unintentional side-effect of causing physicians, fearful of being accused of permitting “opioid overuse”, to prescribe suboptimal doses of opioids to patients in need of them, and to prescribe less effective drugs to patients that are not similarly scheduled. This phenomenon is described in the literature as “opiophobia” or “narcophobia”.
There is a growing recognition in the medical community that a large number of patients suffer from the undertreatment of pain. Among the reasons frequently cited as causative of undertreatment are: (1) the failure to prescribe enough drug at the right dosage interval to reach a steady-state threshold commensurate with the pain relief needed; (2) failure of patients to comply with a given dosage regimen; and (3) the reluctance of many physicians to prescribe analgesics categorized as controlled drugs based on often unfounded concerns of future addiction and fear of regulatory sanctions. For example, it has been reported that with respect to cancer pain, a large percentage of cancer patients suffer debilitating pain despite treatment with analgesics (Cleeland et al., New England Journal of Medicine 1994; 330:592-596).
A number of reported cases of opioid toxicity are a result of inadvertent or unintentional medical use of opioids. It is not uncommon for patients who have difficulty swallowing, to crush the contents of tablets or open a capsule, and swallow the contents with liquids or on soft food. In the case of most immediate release formulations, this generally produces no significant harm, with marginally higher peak concentrations (Cmax) and time to peak concentrations (tmax). However, in the case of extended release opioid formulations, crushing the oral solid dosage form destroys the controlled-release mechanism and results in a rapid surge of drug into the bloodstream, with the entire 12 or 24-hour drug supply released immediately with toxic effects. For this reason, all extended release formulations available for sale in the United States carry a warning to the prescriber and patient not to crush or tamper with the oral solid dosage form (see Prescribing Information for MS Contin®, OxyContin®, Avinza® and Kadian®, Physician's Desk Reference, 2005, Thompson PDR, Montvale, N.J.).
There is therefore a need for a “passive” abuse deterrent system to protect both medical and non-medical users of opioids from intentional or unintentional opioid toxicity, without unnecessary harm to either group from the abuse deterrent technology.
Similarly, abuse deterrent pharmaceutical compositions containing aversive substances can cause serious harm to subjects if injected intravenously and the long terms safety of small amounts of such aversive substances which would be inevitably released in the gastrointestinal tract is unknown.
There is also need, therefore, for novel methods of preventing opioid abuse which do not require the incorporation of aversive and potentially unsafe agents into the formulation.
In 2005, a serious new clinical problem arose with the therapeutic use of extended release opioids, particularly extended release formulations in capsule dosage forms, when co-ingested with alcohol. In this setting, the opioid analgesic was being used for legitimate medical purposes (e.g., to treat pain) and was being ingested as an untampered or intact formulation. Although subjects with chronic pain are discouraged from using opioids with alcohol, the co-ingestion of opioids with alcohol, especially in the setting of intractable pain is widespread. The problem was discovered with a once-a-day extended release formulation of the opioid hydromorphone HCL (Palladone® capsules). Palladone® capsules were introduced in the United States and Canada in 2004. In 2005, Palladone® capsules were withdrawn from the market in both countries due to dose-dumping when co-ingested with alcohol. In a 24-subject study, patients consuming 240 mL of 40% ethanol had a 6-fold mean increase in peak plasma hydromorphone concentration compared with co-ingestion of Palladone® capsules with water. One subject experienced a 16-fold increase when the drug was ingested with 40% alcohol compared with water. Patients consuming 240 mL of 20% ethanol had a 2-fold mean increase in peak plasma hydromorphone concentration. One subject in this group experienced a 6-fold increase when the drug was ingested with 20% alcohol compared with water. In some subjects, 8 ounces of 4% alcohol (equivalent to ⅔ of a typical serving of beer) resulted in almost twice the peak plasma hydromorphone concentration than when the drug was ingested with water. In requesting the withdrawal of Palladone® capsules, FDA noted that the manufacturer of “Palladone® provided FDA data that showed that drinking alcohol while taking Palladone® capsules may cause rapid release of hydromorphone, leading to high drug levels in the body, with potentially fatal effects. High drug levels of hydromorphone may depress or stop breathing, cause coma, and even cause death. The Agency has concluded that the overall risk versus benefit profile of Palladone® is unfavorable due to a potentially fatal interaction with alcohol. Pharmacokinetic data indicate that the co-ingestion of Palladone® and alcohol results in dangerous increases in the peak plasma concentrations of hydromorphone. These elevated levels may be lethal, even in opioid tolerant patients.” (Sloan and Babul, Expert Opinion on Drug Delivery 2006; 3:489-97; http://www.fda.gov/cder/drug/infopage/palladone/default.htm)
FDA has since noted that a number of other capsule formulations of extended release opioids may be similarly vulnerable to dose dumping when co-ingested with alcohol. In vitro studies performed by the FDA have demonstrated that when Avinza® (once-daily extended release morphine) 30 mg was mixed with 900 mL of buffer solutions containing ethanol, the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding Avinza® to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine. (http://www.fda.gov/medwatch/SAFETY/2005/AVINZA_DHC P_Letter_Oct2005.pdf; Sloan and Babul, Expert Opinion on Drug Delivery 2006; 3:489-97)
There is therefore also need, therefore, for novel methods of preventing excessive peak concentrations (dose dumping) of opioids when they are co-ingested for medical purposes at prescribed doses with alcohol.
Extended release formulations have become highly preferable and in some cases, the standard of care for the management of a wide variety of conditions, particularly chronic conditions. Additionally, extended release formulations can make otherwise non-viable pharmaceutical agents (e.g., due to an exceedingly short duration of effect) into viable formulations with clinical and commercial potential.
Extended release dosage forms of opioids may result in fewer interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced quality of life outcomes, and increased control over the management of their medical condition. In addition, such dosage forms may provide more constant plasma concentrations and clinical effects, less frequent peak to trough fluctuations and fewer side effects, compared with short acting or immediate release versions of opioids.
Toxicity from opioids can result from unintentional or intentional tampering of the dosage form. It is not uncommon for patients who have difficulty swallowing, to crush the contents of tablets or open a capsule, and swallow the contents with liquids or on soft food. In the case of most immediate release dosage forms of opioids, this generally produces no significant harm, with marginally higher peak concentrations (Cmax) and time to peak concentrations (tmax). However, in the case of extended release dosage forms of opioids, crushing the oral solid dosage form destroys the controlled-release mechanism and results in a rapid surge of drug into the bloodstream, with the entire 8, 12 or 24-hour drug supply released immediately with toxic effects, or pleasurable effects in the case of a drug abuser. For this reason, all extended release dosage forms available for sale in the United States carry a warning to the prescriber and patient not to crush or tamper with the oral solid dosage form.
There is a need, therefore, for novel methods and pharmaceutical compositions of extended release formulations of opioids to provide continuous relief of signs and symptoms amenable to treatment with the abusable drug, without having to take frequent doses of opioids. There is a need, therefore, for novel methods and pharmaceutical compositions of extended release formulations of opioids that result in fewer interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced quality of life outcomes, and increased control over the management of their medical condition. There is a need, therefore, for novel methods and pharmaceutical compositions of extended release formulations of opioids that result in more constant plasma concentrations and clinical effects, less frequent peak to trough fluctuations and fewer side effects, compared with short acting or immediate release versions of opioids. There is a need for novel methods and pharmaceutical compositions of extended release formulations of opioids that achieve the aforementioned benefits without increasing the risk of toxicity, drug diversion and drug abuse. There is a need for novel methods and pharmaceutical compositions of extended release formulations of opioids that achieve the aforementioned benefits and also provide abuse deterrence.
To date, no extended release formulations of opioids with abuse deterrent technology of any kind have been submitted for Marketing Application (New Drug Application) or been commercialized anywhere in the world. Indeed if prior drug development history is any guide, most such strategies are unlikely to be developed or commercialized and the optimal formulation(s) will likely be apparent only through postmarketing surveillance of several formulations with competing technologies. In addition, regional differences in patterns of abuse mean that different abuse deterrence strategies may be useful in different part of the world. Finally, experience with substance abuses indicates that those who are habitual abusers, particularly those who inject drugs intravenously, have a remarkable ability to defeat abuse deterrence strategies through physical and chemical manipulation of opioids and other drugs of abuse. Such addicts are frequently only one step behind strategies to deter abuse. With the ready access to information from their well knit network and more recently, from websites on how to optimally extract the active agent from pharmaceutical dosage forms and maximize euphoriant effects, the development of abuse deterrent formulations has become a major pharmaceutical, clinical, regulatory and law enforcement challenge.
In view of this, it is not surprising that the Food and Drug Administration's Division of Anesthetic, Analgesic and Rheumatology Drug Products and the U.S. Drug Enforcement Administration have encouraged companies to develop wide ranging abuse deterrent strategies for opioids, particularly extended release opioids and as “inducement”, offered that such products may include in their prescribing information data about their products abuse deterrent properties (FDA Perspectives on Opioid Risk Management. Opioid Risk Management Meeting, Tufts Healthcare Institute, Boston, Mar. 29, 2005; DEA Perspectives on Opioid Risk Management. Opioid Risk Management Meeting, Tufts Healthcare Institute, Boston, Mar. 29, 2005).
Various attempts have been made and are described in prior art to develop abuse-deterrent dosage forms. Clearly there is a need for a delivery system for commonly used oral dosage formulations of drugs, and in particular analgesics such as opioid analgesics, for patients seeking drug therapy and which deters abuse and minimizes or reduces the potential for psychological dependence. In particular, there is a need for formulations that simultaneously provide robust abuse deterrence properties and an extended release pharmacokinetic profile suitable for every 12 or 24 hour oral administration. There is also a need for extended release formulations of opioids that are stable (i.e., do not dose dump) when used at therapeutic doses for medical purposes in conjunction with alcohol. An ideal formulation will provide a extended release pharmacokinetic profile suitable for every 12 or 24 hour release and will be resistant to crushing at room temperature and upon freezing, melting to allow for filtration and/or aspiration into a syringe and extraction with recreational solvents, all without doing harm to pain patients or patients with a substance abuse disorder, through the use of aversive agents or opioid antagonists.
Pharmaceutical dosage forms containing opioids have been used for non-medical purposes in a variety of settings: i) by patients with a disorder requiring treatment with an abusable drug who have developed an addiction disorder following initiation of therapy; ii) by patients with said disorder who had a pre-existing addiction disorder; iii) by patients with an addiction disorder seeking opioids for their reinforcing, rewarding, euphoriant or other mood altering properties.
Non-medical users of opioids are either recreational drug users who may use such agents episodically, or individuals with an addiction disorder who may require frequent maintenance doses. Opioids may be ingested whole, crushed and ingested, crushed or vaporized and snorted or injected intravenously after attempted extraction of the active pharmaceutical ingredient. The manipulation of pharmaceutical dosage forms of opioids has been documented for many decades. For instance, pentazocine (Talwin®), a synthetic opioid was crushed, extracted and injected intravenously by drug addicts.
Addicts and recreational drug users commonly use extended release versions of opioids by a variety of routes of administration. Commonly used methods include 1) parenteral (e.g., intravenous injection), 2) intranasal (e.g., snorting), and 3) episodic or repeated oral ingestion of intact or crushed tablets or capsules.
One mode of abuse can involve the extraction of the opioid component from the dosage form by first mixing the table or capsule with a suitable solvent (e.g., water or alcohol), and then filtering and/or extracting the opioid component from the mixture for intravenous injection. Another mode of abuse of extended release opioids can involve dissolving the drug in water, alcohol or another “recreational solvent” to hasten its release and to ingest the contents orally, in order to provide high peak concentrations and maximum euphoriant effects.
A number of strategies have been introduced to minimize the abuse of mood altering drugs. Primary among these schemes is a legal infrastructure that controls the manufacture, distribution and sale of such drugs. In the United States, opioids are restricted to dispensing on a prescription-only basis. Most of these drugs are “scheduled” as “controlled drugs”, such that distribution of the drug is subject to strict controls and overview. The idea behind scheduling opioids as “controlled” is to ensure that the drugs are dispensed only for the amelioration of legitimate therapeutic maladies, and not for any mood-altering effect “high” or euphoria that may be produced by the drug when used in supra-therapeutic doses or administered by non-approved routes of administration.
While the scheduling of opioids as “controlled drugs” has reduced abuse of the drugs, it has not been entirely successful. For example, some persons who are legitimately prescribed the drugs sometimes divert the drugs to persons seeking their procurement for “recreational uses.” These “recreational drug users” are frequently willing to pay significant sums of money for the drugs. In other cases, certain health professionals, unfortunately, have been found to be culprits in the non-approved distribution of opioid drugs.
It is believed that the most widely used diversion techniques at the “street level” are “doctor shopping” and prescription forgeries. In the case of the former, individuals who may or may not have a legitimate ailment requiring a doctor's prescription for controlled substances, visit numerous doctors, sometimes in several states, to acquire large amounts of controlled substances they abuse or sell to others.
There is a growing recognition in the medical community that a large number of patients suffer from the undertreatment of their medical condition when the treatment involves the use of psychoactive drugs, particularly those drugs which tend to diverted and abused. Scheduling of opioids has also had the unintentional side-effect of causing physicians, fearful of being accused of permitting or even promoting drug abuse and drug overuse, to prescribe suboptimal doses of opioids to patients in need of them, and to prescribe less effective drugs to patients that are not similarly scheduled.
An additional issue with extended release forms of drugs, including opioids is the interaction of the drug, even in an untampered form, when consumed with alcohol. Under such conditions, a number of drugs have demonstrated an in vitro and in vivo propensity for significant dose dumping when they are co-ingested for medical purposes at prescribed doses with alcohol, increasing the potential for drug toxicity and further exacerbating the intensity of the (abusable) drug-alcohol pharmacodynamic interaction.
There is therefore also need, therefore, for novel methods of preventing excessive peak concentrations (dose dumping) of opioids when they are co-ingested for medical purposes at prescribed doses with alcohol.
The present invention also involves oral pharmaceutical compositions of opioids and methods of use thereof which provide reduced variability in rate and extent of absorption when taken with food, compared with the fasted state.
The present invention also involves oral extended release pharmaceutical compositions of opioids and methods of use thereof which provide reduced variability in rate and extent of absorption when taken with food, compared with the fasted state.
Most pharmaceutical companies strive to develop oral pharmaceutical products which can be taken without regard to meal intake, i.e., on an empty stomach or with food. Indeed, it is now a requirement of both U.S. and E.U regulatory guidance's to conduct studies of all new chemical entities to determine the influence of concurrent food intake on the bioavailability of products. Concurrent intake of food in so called “fed-fasted” human bioavailability studies may increase, decrease or have no effect on the bioavailability of the pharmaceutical products. Accordingly, the prescribing information guides both the prescriber and the patient on the appropriate use of the pharmaceutical product.
The issue of food effects on oral bioavailability has particular importance with oral extended release products, due to the possibility of “dose dumping” where the is potential that a portion or a substantial portion of the dose intended to be released gradually over time (e.g., over 8, 12 or 24 hours) may be released instantaneously or rapidly, such that the peak plasma concentration of the drug (peak exposure) will be substantially increased, resulting in toxicity and the duration of effect will be significantly reduced, potentially resulting in reduced duration of therapeutic effect. The ability to take the drug without regard to food intake and in the case of extended release pharmaceutical products, the absence of dose dumping has been found to be a significant patient benefit and a competitive marketing advantage. It is not uncommon to see pharmaceutical advertising targeted to medical practitioners which states “no food effect”, “may be taken on an empty stomach or with food” and “may be taken without regard to food” and “no change in bioavailability with food”.
The U.S. prescribing information for OxyContin™ (oxycodone ER) states “Food has no significant effect on the extent of absorption of oxycodone from OxyContin. However, the peak plasma concentration of oxycodone increased by 25% when a OxyContin 160 mg Tablet was administered with a high-fat meal.”
The U.S. prescribing information for Opana™ ER (oxymorphone ER) states “two studies examined the effect of food on the bioavailability of single doses of 20 and 40 mg of OPANA ER in healthy volunteers. In both studies, after the administration of OPANA ER, the Cmax was increased by approximately 50% in fed subjects compared to fasted subjects. A similar increase in Cmax was also observed with oxymorphone solution.”
In summary, many opioids in extended release form have a potentially clinically important food effect.
There is therefore a need for oral immediate release pharmaceutical compositions, and particularly extended release pharmaceutical compositions with consistent bioavailability regardless of administration in the fed or fasted state.
There is a need for methods and pharmaceutical compositions of pharmaceuticals and therapeutic agents that provide an extended release profile, preferably suitable for every 8, 12 or 24 hour oral administration. There is a need for methods and pharmaceutical compositions of opioids that provide an extended release profile. There is also a need for methods and pharmaceutical compositions of opioids that provide an abuse deterrent profile. In particular, there is a need for methods and pharmaceutical compositions of opioids that simultaneously provide abuse deterrence properties and extended release profiles, preferably suitable for every 8, 12 or 24 hour oral administration. There is also a need for extended release formulations of pharmaceuticals and therapeutic agents, and opioids that are stable (i.e., do not dose dump) when used at therapeutic doses for medical purposes in conjunction with alcohol. There is also a need for extended release formulations of pharmaceuticals and therapeutic agents, and opioids that provide a extended release pharmacokinetic profile suitable for every 8, 12 or 24 hour release and will be resistant to crushing at room temperature and upon freezing, melting to allow for filtration and/or aspiration into a syringe and extraction with recreational solvents. There is also a need for extended release formulations of pharmaceuticals and therapeutic agents, and opioids that provide a extended release pharmacokinetic profile suitable for every 8, 12 or 24 hour release and will be resistant to crushing at room temperature and upon freezing, melting to allow for filtration and/or aspiration into a syringe and extraction with recreational solvents, all without doing harm to patients or patients with a substance abuse disorder, through the use of aversive agents or antagonists.